Risk factors for locoregional recurrence (LRR) after neoadjuvant chemotherapy: Pooled analysis of prospective neoadjuvant breast cancer (BC) trials

Abstract

Background: LRR after neoadjuvant chemotherapy (NACT) for BC may impact patient's outcome. This study aimed to evaluate the rates of LRR as first event after NACT and to identify independent predictors of LRR. Methods: A total of 10075 women with primary BC and available follow-up from 9 prospective neoadjuvant trials were included in the pooled analysis. The main endpoint was cumulative incidence rates of LRR as first event after NACT; distant recurrence, secondary malignancy or death was defined as competing event. To identify predictors of LRR, surgery type, pathological complete response (pCR=ypT0 ypN0), BC subtypes and other risk factors were evaluated using Fine-Gray's regression model. The two-sided significance level was set to α = 0.05. Results: After a median follow-up in the entire cohort of 67 months (range 0-215 months), 959 (9.5%) LRRs as first event were observed. Age ( < =50 vs > 50 years; p < 0.001), clinical nodal status (cN- vs cN+; p < 0.001), tumour grade (G1-2 vs G3; p = 0.001), pCR (no vs yes; p < 0.001) and BC subtypes (HR+/HER2- vs HR+/HER2+, HR-/HER2+, TNBC; p < 0.001) but not surgery type (BCS vs mastectomy; p = 0.514) were significant independent predictors of LRR in multivariate analysis. LRR rates among BC subtypes were lower in pts achieving pCR vs non-pCR: HR+/HER2- (3.9% vs 5.9%; HR = 0.56 [95%CI 0.32-0.98]; p = 0.043); HR+/HER2 + (4.8% vs 8.1%; HR = 0.61 [95%CI 0.37-1.02]; p = 0.058); HR-/HER2 + (3.1% vs 14.8%; HR = 0.22 [94%CI 0.12-0.39]; p < 0.001) and in TNBC (4.2% vs 18.5%; HR = 0.25 [95%CI 0.18-0.35]; p < 0.001). Within the non-pCR subgroup, LRR rates were significantly higher in pts with HR-/HER2+ and TNBC vs HR+/HER2- BC (HR = 2.34 [95%CI 1.83-2.99]; p < 0.001 and HR = 3.02 [95%CI 2.54-3.60]; p < 0.001, respectively) as well as in pts treated with mastectomy than with BCS (HR = 1.22 [95%CI 1.06-1.1.41]; p = 0.007). Conclusions: Young age, node-positive and G3 tumours as well as non-pCR status and TNBC were found to significantly increase the risk of LRR as first event after NACT. Pts with HR-/HER2+ and TNBC not achieving pCR were at highest risk of LRR. Hence, these BC subtypes might be considered for additional post-neoadjuvant treatment approaches. Legal entity responsible for the study: German Breast Group (GBG). Funding: Has not received any funding. Disclosure: M. Untch: Honoraria (institution), non-financial support: Abbvie; Honoraria (institution), non-financial support: Amgen GmbH; Honoraria (institution), non-financial support: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), non-financial support: Celgene GmbH; Honoraria (institution), non-financial support: Daiji Sankyo; Honoraria (institution), non-financial support: Eisai GmbH; Honoraria (institution), non-financial support: Janssen Cilag; Honoraria (institution), non-financial support: TEVA Pharmaceuticals Ind Ltd; Honoraria (institution): Lilly Deutschland; Honoraria (institution), non-financial support: Sividon Diagnostics; Honoraria (institution), non-financial support: MSD Merck; Honoraria (institution), non-financial support: Mundipharma; Honoraria (institution), non-financial support: Myriad Genetics; Honoraria (institution), non-financial support: Odonate; Honoraria (institution), non-financial support: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), non-financial support: Novartis; Honoraria (institution), non-financial support: Roche Pharma AG; Honoraria (institution), non-financial support: Sanofi Aventis Deutschland GmbH. C. Hanusch: Honoraria (self), Outside the submitted work: Roche; Honoraria (self), Outside the submitted work: Pfizer; Honoraria (self), Outside the submitted work: Novartis; Honoraria (self), Outside the submitted work: Celgene; Honoraria (self), Outside the submitted work: Lilly; Honoraria (self), Outside the submitted work: AstraZeneca. P.A. Fasching: Research grant / Funding (institution), The Work Under Consideration for Publication: Novartis; Research grant / Funding (institution), The Work Under Consideration for Publicat on: Biontech; Honoraria (self), The Work Under Consideration for Publication: Novartis; Honoraria (self), The Work Under Consideration for Publication: Roche; Honoraria (self), The Work Under Consideration for Publication: Pfizer; Honoraria (self), The Work Under Consideration for Publication: Celgene; Honoraria (self), The Work Under Consideration for Publication: Daiichi-Sankyo; Honoraria (self), The Work Under Consideration for Publication: TEVA; Honoraria (self), The Work Under Consideration for Publication: AstraZeneca; Honoraria (self), The Work Under Consideration for Publication: Merck Sharp & Dohme; Honoraria (self), The Work Under Consideration for Publication: Myelo Therapeutics; Honoraria (self), The Work Under Consideration for Publication: Macrogenics; Honoraria (self), The Work Under Consideration for Publication: Eisai; Honoraria (self), The Work Under Consideration for Publication: Puma; Research grant / Funding (institution), The Work Under Consideration for Publication: Cepheid. S. Seiler: Honoraria (self), presentations: Roche; Advisory / Consultancy: Amgen GmbH; Advisory / Consultancy: Hexal; Honoraria (self): Mundipharma; Non-remunerated activity/ies: Novartis. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. H. Tesch: Honoraria (self): Vifor; Honoraria (self): Roche; Honoraria (self): Amgen. C. Jackisch: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self): Roche. A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. T. Link: Honoraria (self): Amgen; Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Pharma Mar; Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self), Non-remunerated activity/ies: Roche. J. Huober: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Abbvie. K. Rhiem: Honoraria (self): Tesaro; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca. S. Loibl: Honoraria (institution), Research grant / Funding (institution), The Work Under Consideration for Publication: Roche; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: AbbVie; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside t e submitted work: Amgen; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: AstraZeneca; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Celgene; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Novartis; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Pfizer; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Seattle Genetics; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Teva; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Vifor; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: PRIME; Honoraria (institution), Research grant / Funding (institution), Relevant financial activities outside the submitted work: Daiichi; Licensing / Royalties, Intellectual Property - Patents & Copyrights: EP14153692.0 pending. All other authors have declared no conflicts of interest.